Abstract 3025: Optimization of therapeutic index of SGR-3515, a first-in-class Wee1/Myt1 inhibitor through intermittent dosing for monotherapy and combination with chemotherapy in xenograft tumor models

Abstract Background: Cancer cells often have deregulated G1-S phase in cell cycle and rely on the G2-M checkpoint to delay mitosis allowing for completed DNA damage repair. Wee1 and Myt1 kinases regulate G2 to M phase transition by inhibitory phosphorylation of cyclin dependent kinase (CDK1) to prevent premature entry to mitosis. Small molecule inhibitors targeting either Wee1 or Myt1 have shown promising clinical benefit in solid tumors as a monotherapy and/or combination therapy. Emerging evidence suggests that Wee1 and Myt1 have a synthetic lethal relationship in tumor cells, and Myt1 upregulation contributes to acquired resistance to Wee1 inhibitors. Here we describe the superior anti-tumor activity of SGR-3515, a first-in-class Wee1/Myt1 inhibitor, compared to single inhibition of Wee1 or Myt1 as a monotherapy, synergistic combination with chemotherapy and optimization of dosing schedule to achieve improved therapeutic index in xenograft tumor models. Methods: SGR-3515 was identified internally using Schrödinger’s computational platform. Its binding affinity to Wee1 or Myt1 and inhibition potency of kinase activity was measured by surface plasmon resonance (SPR) assay and ADP-Glo kinase activity assay, respectively. SGR-3515 effects on DNA damage and cell cycles were investigated in tumor cell lines using gH2Ax and DNA staining high content imaging assays, respectively. The cellular target engagement was measured by pCDK1 Y15 for Wee1 inhibition and pCDK1 T14 for Myt1 inhibition in tumor cell lines. The in vivo anti-tumor activity was evaluated in cell line derived xenograft models. Results: SGR-3515 is a novel and potent small molecule inhibitor of Wee1/Myt1. The co-inhibition of Wee1 and Myt1 induces rapid DNA damage and causes significant tumor cell apoptosis. SGR-3515 demonstrates superior anti-tumor activity in vivo in xenograft models compared to single inhibition of Wee1 or Myt1 alone, consistent with the Wee1 and Myt1 synthetic lethal relationship. Furthermore it suppresses the acquired resistance associated with a Wee1 inhibitor (ZNc3). Optimization of intermittent dosing schedule of SGR-3515 allows sufficient recovery of Wee1 inhibition mediated myelosuppression while maintaining similar anti-tumor activity as the continuous dosing in xenograft tumor models. Intermittent dosing of SGR-3515 in combination with carboplatin achieved synergistic anti-tumor activity without significantly worsening hematological effects. Conclusions: The robust anti-tumor activity of SGR-3515, a first-in-class Wee1/Myt1 inhibitor confirms the synergy of Wee1 and Myt1 co-inhibition. SGR-3515 dosing schedule optimization improves therapeutic index as a monotherapy and in combination with Carboplatin. The preclinical data supported the progression of SGR-3515 to clinical study (NCT06463340). Citation Format: Shaoxian Sun, Felicia Gray, Sarah Silvergleid, Robert Pelletier, Lin Tang, Andrew Placzek, Jiashi Wang, Pieter Bos, Jennifer Knight, Anthony Clark, Zhijian Liu, Naveen Thakral, Aleksey Gerasyuto. Optimization of therapeutic index of SGR-3515, a first-in-class Wee1/Myt1 inhibitor through intermittent dosing for monotherapy and combination with chemotherapy in xenograft tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3025.